Natural mechanisms of repair, healing and augmentation are similar for bone and cartilage. (U.S. Pat. No. 5,686,116) Although repair, healing and augmentation require a complex series of events that are not well defined, it is known that specific, naturally occurring factors are required to achieve these objectives. Such factors are released or migrate into the injured area, and stimulate osteoblasts and chondrocytes and odontoblasts in bone and cartilage to stimulate matrix formation and remodeling of the wounded area. (ten Dijke et al., Bio/Technology, 7:793-798 (1989))
Living bone tissue is continuously being replenished by the processes of resorption and deposition of bone matrix and minerals. This temporally and spatially coupled process, termed bone remodeling, is accomplished largely by two cell populations, the osteoclasts and osteoblasts. (U.S. Pat. No. 5,656,598, incorporated by reference herein in its entirety) The remodeling process is initiated when osteoclasts are recruited from the bone marrow or the circulation to the bone surface and remove a disk-shaped packet of bone. The bone matrix and mineral is subsequently replaced by a team of osteoblasts recruited to the resorbed bone surface from the bone marrow. Osteoblasts are derived from local mesenchymal (stromal) precursors which differentiate into osteoblasts.
New bone can be formed by three basic mechanisms: osteogenesis, osteoconduction and osteoinduction. (U.S. Pat. No. 5,464,439 incorporated by reference herein in its entirety) In osteogenic transplantation, viable osteoblasts and peri-osteoblasts are moved from one body location to another where they establish centers of bone formation. Cancellous bone and marrow grafts provide such viable cells. TGF-beta has been shown to stimulate proliferation and matrix synthesis of osteoblastic cells (Centrella, et al. (1987) J. Biol. Chem. 262:2869-2874) and to inhibit the formation and activity of osteoclastic cells (Chenu, et al. (1988) Proc. Natl. Acad. Sci. U.S.A. 85:683-5687; Kiebzak et al. (1988) J. Bone Min. Res. 3:439-446), and to stimulate local bone formation in vivo. (Joyce, et al. (1990) J. Cell. Biol. 110:2195-2207; Noda and Camilliere (1989) Endocrinology 124:2991-2294). Other factors reported to stimulate bone growth include bone morphogenetic proteins (WO 88/00205), insulin-like growth factor (IGF) (Endocrinol. Metab. 13:E367-72,1986), and parathyroid hormone (J. Bone & Min. Res. 1:377-381, 1986).
Members of the bone morphogenetic protein family have been shown to be useful for induction of cartilage and bone formation. For example, BMP-2 has been shown to be able to induce the formation of new cartilage and/or bone tissue in vivo in a rat ectopic implant model, see U.S. Pat. No. 5,013,649; in mandibular defects in dogs, see Toriumi et al., Arch. Otolaryngol Head Neck Surg., 117:1101-1112 (1991); and in femoral segmental defects in sheep, see Gerhart et al., Trans Orthop Res Soc, 16:172 (1991). Other members of the BMP family have also been shown to have osteogenic activity, including BMP-4, -6 and -7 (see Wozney, Bone Morphogenetic Proteins and Their Gene Expression, in Cellular and Molecular Biology of Bone, pp. 131-167 (Academic Press, Inc. 1993)). BMP proteins have also been shown to demonstrate inductive and/or differentiation potentiating activity on a variety of other tissues, including cartilage. (U.S. Pat. No. 5,700,774, hereby incorporated by reference in its entirety.
In the transplantation of large segments of cortical bone or allogenic banked bone, direct osteogenesis does not occur. Rather, osteoconduction occurs wherein the dead bone acts as a scaffold for the ingrowth of blood vessels, followed by the resorption of the implant and deposition of new bone. This process is very slow however, often requiring years to reunite a large segmental defect.
Osteoinduction is the phenotypic conversion of connective tissue into bone by an appropriate stimulus. As this concept implies, formation of bone can be induced at even non-skeletal sites. Osteoinduction is preferred over osteoconduction, as grafts of this type are typically incorporated into the host bone within a two-week period. In contrast, osteoconductive grafts have been found to be non-incorporated as long as one year after implantation. In order to provide an environment suitable for osteoinduction, a material should be selected which is not only capable of inducing osteogenesis throughout its volume, but is also biocompatible, non-inflammatory, and possesses the ability to be ultimately resorbed by the body and replaced with new, natural bone.
Among the pathological conditions associated with abnormal bone cell function are osteoporosis, osteoarthritis, Paget's disease, osteohalisteresis, osteomalacia, periodontal disease, bone loss resulting from multiple myeloma and other forms of cancer, bone loss resulting from side effects of other medical treatment (such as steroids), and age-related loss of bone mass. Inadequate organic matrix mass places an individual at risk of skeletal failure such that bone fractures can result from the minimal trauma of everyday life. Such fractures cause significant illness, or morbidity, inasmuch as there is insufficient repair or healing of the fractures. In certain pathologic conditions, osteoclast-mediated resorption is not regulated by osteoblasts but is driven by cancer cells, infecting organisms or the host's immune cells. In those disease conditions, resorption of bone far exceeds bone formation. Such accelerated osteoclastic activity leads to excessive release of calcium from the inorganic mineral in bone, with a concomitant net loss of skeletal mass, often with an attendant disturbance in calcium homeostasis in the form of elevated blood levels of calcium. (U.S. Pat. No. 5,686,116, incorporated by reference herein in its entirety.)
Although methods for directing new bone formation are known, improved methods that provide for accelerated bone growth are needed. For example, currently approved therapeutic agents for osteoporosis are antiresorptives. As such, they are not as effective in patients with established osteoporosis of either type (decreased bone density with fractures of the vertebrae and/or hip), or in patients with Type II osteoporosis. In addition, the most accepted preventive agent for osteoporosis currently in use is estrogen therapy, which is not an acceptable therapeutic agent for women with a history of breast cancer or endometrial cancer or for men with osteoporosis.
Similarly, successful implantation and function of bone implants depends on bonding of the adjacent bone to the implant. (U.S. Pat. No. 5,686,116) Such bonding requires bone rep air by the formation of new matrix components at the interface between the implant and the bone proximate to the implant. An estimated ten percent of bone and joint prosthetic devices that are placed in people fail to function due to non-bonding of the bone to an implant. The resulting disability often requires reoperation and reimplantation of the device. Furthermore, five to ten percent of all bone fractures are never repaired. Although many methods have been proposed to cure these non-healing bone fractures, none has yet proven to be satisfactory. Based on all of the above, there clearly exists a need in the art for improved methods that provide for accelerated bone growth.
Cartilage is a specialized type of dense connective tissue consisting of cells embedded in a matrix. There are several kinds of cartilage. (U.S. Pat. No. 5,736,372, herein incorporated by reference in its entirety.) Translucent cartilage having a homogeneous matrix containing collagenous fibers is found in articular cartilage, in costal cartilages, in the septum of the nose, in larynx and trachea. Articular cartilage is hyaline cartilage covering the articular surfaces of bones. Costal cartilage connects the true ribs and the sternum. Fibrous cartilage contains collagen fibers. Yellow cartilage is a network of elastic fibers holding cartilage cells which is primarily found in the epiglottis, the external ear, and the auditory tube. Cartilage is tissue made up of extracellular matrix primarily comprised of the organic compounds collagen, hyaluronic acid (a proteoglycan), and chondrocyte cells, which are responsible for cartilage production. Collagen, hyaluronic acid and water entrapped within these organic matrix elements yield the unique elastic properties and strength of cartilage. Chondrocytes produce both Type I and Type II collagens. Type II collagen is not found in bone, whereas Type I collagen is found in bone. (U.S. Pat. No. 5,686,116) It has previously been shown that the endogenous growth factors TGF beta and BMP induce both new cartilage and bone formation. Wozney et al. Science, 242:1528-1533 (1988) and Sporn et al. J. Cell Biol. 105:1039-1045 (1987).
In cartilage, collagen synthesis is required for repair, healing and augmentation, as well as for the successful bonding of grafts and prosthetic devices. (U.S. Pat. No. 5,686,116) Collagen is the major structural protein responsible for the architectural integrity of cartilage. Thus, an adequate supply of chondrocytes is essential in order to produce sufficient amounts of collagen for repair, healing, and augmentation of cartilage. Other, noncollagen proteins, such as osteonectin, fibronectin and proteoglycans are also important for cartilage repair.
Cells such as synoviocytes that are found in joint spaces adjacent to cartilage have an important role in cartilage metabolism. Synoviocytes produce metallo-proteinases, such as collagenases that are capable of breaking-down cartilage. TGF beta is known to inhibit cell-release (and probably synthesis) of metallo-proteinases and to induce chondrocytes (cartilage forming cells) to produce new matrix components and inhibit production of cartilage destructive enzymes so as to effect cartilage repair, healing and augmentation. Spom et al. (1987). It has also been shown that mice deficient in parathyroid hormone-related peptide (PTHrP) exhibit abnormal cartilage maturation, indicating that PTHrP is an essential factor for chondrocyte development and maturation. (U.S. Pat. No. 5,700,774)
Cartilage implants are often used in reconstructive or plastic surgery such as rhinoplasty. There is a need in the art for methods that increase chondrocyte proliferation and collagen synthesis, and thus inhibit cartilage destruction and enhance cartilage repair. Such methods would increase the clinical utility of cartilage repair including but not limited to cartilage grafts and healing of cartilage grafts.
Although some of the above methods have met with limited success, there remains a need in the art for improved methods for enhancing bone and cartilage repair, healing and augmentation, and for enhancing the attachment and fixation of bone and cartilage implants.